Risk-Based cGMPs: Defining Risk and Change the focus from controlling GMP requirements to controlling

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    Risk-Based cGMPs: Defining Risk and Quality

    April 22, 2003 Bruce Burlington

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    Risk-Based Approach to cGMPs

    PhRMA Welcomes the FDA’s Initiative

    Science-based risk management & integrated quality systems cGMPs approach

    Attention focused on control of critical manufacturing points that define quality

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    Risk-Based Approach to cGMPs Task Force

    Bruce Burlington Wyeth

    Dave Haggard Merck

    Ed Kaminski Wyeth

    Frances Sakers Wyeth

    John Grazal Astra Zeneca

    Janice Whitaker GSK

    Erika King PhRMA

    Alice Till PhRMA

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    Questions We Asked

    1. What is the meaning of risk? 2. How do we maintain high quality standards? 3. What regulations or practices are affected? 4. What are the benefits to this new approach? 5. How does industry collaborate with FDA Field and

    Center Offices? 6. How would this affect new technology? 7. How does this fit with CMC and other initiatives?

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    Task Force Approach

    1. Define the Ideal State: Phase in changes 2. Guiding principles – as we move forward:

    Improve efficiency for both FDA and industry Identify the meaning and scope of “risk-based” Risk to whom? Patient centered: safety, efficacy,& availability

    3. Identify additional benefits and behavioral changes

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    Meaning and Scope of Risk-based

    The focus must be from the patients viewpoint. We believe the patient wants pharmaceutical products to: 1. Be available when needed 2. Be “fit for use,” meaning

    Safe Effective Readily identifiable Convenient to use

    Quality can be defined as consistently and reliably meeting patient needs.

    Safety and efficacy of the product for use relates to the product used to generate clinical data.

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    Improve Efficiency

    Efficient (and effective) GMPs allow focus on: Critical vs. non-critical parameters. Non-patient oriented controls may divert effort away from adequate drug product quality, availability and effective problem resolution.

    Quality Systems Critical Process Parameters Critical Control Points

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    Additional Benefits

    Unites the CMC submission and cGMPs on requirements, review and interpretation

    Critical quality parameters and critical control points require special consideration (as opposed to non-critical parameters)

    Provides a framework for product specific SUPAC

    Assists in an equitable and consistent interpretation by both industry and FDA

    eg. Technical dispute resolution process

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    Behavioral Changes

    Industry must provide full development reports and design product quality into manufacturing and testing procedures.

    FDA must focus on critical process and/or control parameters that may impact product safety and efficacy in NDA reviews and inspections.

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    An Ideal State

    A Paradigm Shift: Change the focus from controlling GMP requirements to controlling the “Risk to the Patient.”

    The Challenge to FDA and Industry: Regulations must be compatible with satisfying patient requirements for safety, efficacy & availability.

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    nReview each System (FDA Systems Based Inspection Program) using the Risk-Based GMP Framework. nReview GMP Framework in a risk-based environment. nReview Examples of current GMP activities of concern.

    Tier 2: Acceleration

    6-12 months

    nOperational issues exist around the guidance documents themselves and the interpretation by FDA investigators. Many of the current guidance documents were not constructed with a consideration of risk models, e.g. High Purity Water Systems (1993) and Cleaning Process Validation (1993). All of the “Guide to Inspection of…” could be reviewed with an emphasis on considering risk (patient safety, use). Additionally, the actual field interpretation of the documents has been noted to go beyond the actual guidance. Specific examples of this could be provided. An emphasis could be on a negotiation process between the Center and the firm with science vs. compliance issues defaulting to science.

    Tier 1: A Beginning 6 months

    FDA GMP Inspection Based IssuesTime Frames

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    nThe current 21 CFR 210-11 is revised, retaining assurance the product is safe and efficacious. nThe NDA CMC section development report supports company’s risk management strategy. nIdentify the Risk level (low, medium, high) for probability and severity of impact on patient safety and efficacy,

    o Critical Control Points o Interim Specifications o Critical Process Parameters o Quality Systems

    nThe amount and content of documentation to support each risk level is proportional to the risk level. nLow risk changes do not require supplements as long as the resultant change is still rated as low risk. nDocument and trend all data for an overall Annual Product Risk Review, on file and available for FDA inspections. nPAT, etc. – reduced or eliminated end product testing.

    Tier 3: The Ideal

    State 1-3 years

    FDA GMP Inspection Based IssuesTime Frames

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    Next Steps for the Journey

    The FDA and industry work in collaboration employing risk-based management principles to:

    Measure the significance of production issues against medical need and product availability. Guide in the implementation, review and application of technological advances. Scrutinize changes and the change approval process to allow for other means of pre-approval review. Appropriately target audit and inspection plans (duration and intensity) based on inherent risks of product/site compliance.

    Risk-Based cGMPs:Defining Risk and Quality April 22, 2003 Risk-Based Approach to cGMPs Risk-Based Approach to cGMPs Task Force Questions We Asked Task Force Approach Meaning and Scope of Risk-based Improve Efficiency Additional Benefits Behavioral Changes An Ideal State Next Steps for the Journey


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